Gastrointestinal (GI) disorders such as inflammatory bowel diseases (Crohn's Disease, ulcerative colitis) and irritable bowel disorders affect over 16 million patients, accounting for nearly 5 million physician's office visits and nearly 10 million prescriptions (NIDDK statistics). Some GI disorders are especially prevalent in older populations. Over the past two decades, it has become clear that, in many cases, these disorders can be caused by or exacerbated by disruptions in the microbial community that inhabits the GI tract. Concurrently, appreciation has grown for using live biologics therapies such as probiotics and, more recently, fecal transplants, in attempts to restore the normal intestinal microbiota. In many cases, these approaches have proven to be quite successful, and thus are becoming more and more widespread. In 2007, the National Institutes of Health launched The Human Microbiome Project - an attempt to fully characterize the microbiota on the skin, in the mouth and nose, and within the gastrointestinal and urogenital tracts in humans. As result, we have gained an appreciation for the complexity of the intestinal microbiota and the role it plays in human health. However, we still know relatively little about how human physiology, especially that associated with reproductive hormones, affects the intestinal microbiota. This project will help to fill that gap by testing the hypothesis that the composition f the intestinal microbiota is affected by changes in circulating estrogen. Our goals are to examine how changes in circulating estrogen affect the composition of the microbiota inhabiting the digestive tract and the mechanism(s) by which such effects are mediated. We will achieve these goals by performing experiments associated with three Specific Aims: 1) Examine the effects of hormone manipulations on intestinal microbiota; 2) Examine the roles of the ? and ? sub-types of estrogen receptors in changing the microbiota; and 3) Examine the effects of a lack of ovarian estrogen on intestinal microbiota. Our general approach will be to manipulate circulating estrogen in female prairie voles and examine the effects of those manipulations on intestinal microbiota composition. Prairie vole females do not display an estrous cycle, allowing us to layer hormone manipulations over low but constant circulating estrogen without the need for surgical intervention to reduce the potential confound of fluctuating estrogen and progesterone. This approach also has the advantage of allowing examination of the recovery of the microbiota after estrogen treatment is ended and the normal, but low and constant, baseline levels of ovarian estrogen are restored.